Mechanics of Monolayer Migration

描述（由申请人提供）：肺中的细胞通常不是作为单个实体迁移，而是作为集体片、管、股或簇迁移。但是，每个细胞如何与近邻细胞协调其迁移还没有完全理解。我们在这里提出一个假设，即协调细胞迁移的一个经常被忽视但仍然重要的特征是，每个组成细胞可能会受到最近邻居的物理约束（堵塞）。干扰假说看似简单，但却能做出令人惊讶的、复杂的、可检验的先验的机械预测。它预测：1)一体化单层内的细胞如果没有邻近细胞的协同运动就无法迁移；2)这种合作延缓了系统动力学，并通过在组织的多个尺度上自发出现的戏剧性的异质力链来实现；3)在呼吸和机械通气过程中，黏着相互作用的减少、压应力的减少或潮汐变形的增加，都有助于促进细胞的疏解和分解，并且都可以用统一的干扰相图来描述。使用一个独特的实验平台的原型-单层应力显微镜-我们已经获得了支持这一新的物理图像的初步数据。如果它被证明具有预测能力，那么这一假说将把上皮和内皮单层生理学中的集体薄片迁移的各个方面，以及修复、屏障功能、纤维化和上皮-间质转化（EMT）的各个方面汇集在一个机制标题下。

DESCRIPTION (provided by applicant): Cells in the lung often migrate not as individual entities but as collective sheets, ducts, strands, or clusters. But how each cell can coordinate its migration with that of immediate neighbors has defied full comprehension. We propose here the hypothesis that a much overlooked but nonetheless central feature of coordinated cellular migration is that each constituent cell can become physically constrained (jammed) by nearest neighbors. The jamming hypothesis is deceptively simple, yet makes mechanistic predictions a priori that are surprising, complex, and testable. It predicts: 1) that a cell within the integrated monolayer cannot migrate without cooperative motions of its immediate neighbors; 2) that this cooperativity retards system dynamics, and does so through spontaneous emergence of dramatically heterogeneous force chains that ripple through the system at multiple scales of organization; and 3) that decreasing adhesive interactions, or decreasing compressive stresses, or increasing tidal deformations as occur in breathing and mechanical ventilation, all serve to pro- mote cell unjamming and disaggregation, and are all described by a unified jamming phase diagram. Using a prototype of a unique experimental platform -Monolayer Stress Microscopy- we have obtained preliminary data supporting this novel physical picture. If it is shown to have predictive power, this hypothesis would bring together under one mechanistic rubric diverse aspects of collective sheet migrations in epithelial and endothelial monolayer physiology, as well as in repair, barrier function, fibrosis, and the epithelial-mesenchymal transition (EMT). PUBLIC HEALTH RELEVANCE: Recent technical and conceptual advances from our team1-13 lead to the suggestion that mechanics of the cellular monolayer in the lung, and in other organ systems as well, may be dominated by a change of state called the jamming transition. This new perspective leads logically to important new questions. In normal physiology, for example, do cellular monolayers tend to form solidlike aggregated sheets -with excellent barrier function and with little possibility of cell invasion or escape- because constituent cells are jammed? In pathophysiology, do certain cell populations become fluidlike and permissive of paracellular leak, transformation, invasion or cell escape because they become unjammed? To answer these questions, our interdisciplinary team will test the jamming hypothesis in well-characterized endothelial and epithelial monolayer systems. And to test the limits of applicability of the jamming hypothesis, we will study four well-characterized stable cell lines pre- and post-EMT. These experimental studies will be made possible by an enabling new technology that we pro- pose to develop: Monolayer Stress Microscopy.